channelopathies: Navigating from genotype to neural circuit dysfunction.

The gene is strongly associated with epilepsy and plays a central role for supporting cortical excitation-inhibition balance through the expression of Na1.1 within inhibitory interneurons. The phenotype of disorders has been conceptualized as driven primarily by impaired interneuron function that predisposes to disinhibition and cortical hyperexcitability. However, recent studies have identified gain-of-function variants associated with epilepsy, and the presence of cellular and synaptic changes in mouse models that point toward homeostatic adaptations and complex network remodeling. These findings highlight the need to understand microcircuit-scale dysfunction in disorders to contextualize genetic and cellular disease mechanisms. Targeting the restoration of microcircuit properties may be a fruitful strategy for the development of novel therapies.